Over the last decade, major advances have been made in the understanding of the biology of the mammalian tachykinin neuropeptides. It is now well established that substance-P (1), neurokinin A (NKA) (2), and neurokinin B (NKB) (3), all of which share a common C-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2, (Nakanishi S., Physiol. Rev., 67: 117 (1987)), are widely distributed throughout the periphery and central nervous system (CNS) where they appear to interact with at least three receptor types referred to as NK.sub.1, NK.sub.2, and NK.sub.3 (Guard S., et al., Neurosci. Int., 18: 149 (1991)). Substance-P displays highest affinity for NK.sub.1 receptors, whereas NKA and NKB bind preferentially to NK.sub.2 and NK.sub.3 receptors, respectively. Recently, all three receptors have been cloned and sequenced and shown to be members of the G-protein-linked "super family" of receptors (Nakanishi S., Annu. Rev. Neurosci., 14: 123 (1991)).
Substance-P is the best known of the mammalian tachykinins and has been shown to display preferential affinity for the NK.sub.1 tachykinin receptor (Guard S., Watson S. P., Neurochem. Int., 18: 149 (1991)). Substance-P and the other tachykinins are suggested to play a major role in a variety of biological processes including pain transmission, vasodilation, bronchoconstriction, activation of the immune system, and neurogenic inflammation (Maggi C. A., et al., Auton. Pharmacol., 13: 23 (1993)).
However, to date, a detailed understanding of the physiological roles of tachykinin neuropeptides has been severely hampered by a lack of selective, high affinity, metabolically stable tachykinin receptor antagonists that possess both good bioavailability and CNS penetration. Although several tachykinin receptor antagonists have been described (Tomczuk B. E., et al., Current Opinions in Therapeutic Patents, 1: 197 (1991)), most have been developed through the modification and/or deletion of one or more of the amino acids that comprise the endogenous mammalian tachykinins such that the resulting molecules are still peptides that possess poor pharmacokinetic properties and limited in vivo activities.
Since 1991, a number of high-affinity nonpeptide NK.sub.1 tachykinin receptor antagonists have been identified primarily as a result of the screening of large comopund collections using high throughput radioligand binding assays. These include the fiollowing: the quinuclidine derivative, CP-96345 [Snider R. M., et al., (Science, 251: 435 (1991)); the piperidine derivative, CP-99994 (McLean S., et al., J. Reg. Peptides, S12- (1992); the perhydroisoindoione derivative, RP-67580 (Garret C., et al., Natl. Acad. Sci., U.S.A., 88: 10208 (1991)); the steroid derivative, WIN 51708 (Lawrence K. B., et al., J. Med. Chem., 35: 1273 (1992)); the piperidine derivative, SR-140333 (Oury-Donat F., et al., Neuropeptides, 24: 233 (1993)); and a tryptophan derivative (Macleod A. M., et al., J. Med. Chem., 36: 2044 (1993)).
FK888, a di-peptide with high affinity for the NH.sub.1 receptor, was rationally designed from the octapeptide [D-Pro.sup.4, D-Trp.sup.7,9,10, Phe.sup.11 ]SP(4-11) (Fujii T., et al., Neuropeptides, 22: 24 (1992)). Schilling, et al., have been described a series of piperidines as NK.sub.1 receptor antagonists derived from a peptide/template approach (Schlling W., et al., XIIth International Symposium on Medicinal Chemistry, Basel, September 1992, Abstract ML-11.3).
Substance-P is widely distributed throughout the periperhy and central nervous system. It is believed to mediate a variety of biological actions, via an interaction with three receptor types referred to as NH.sub.1, NK.sub.2, and NK.sub.3, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-construction, activation of the immune system and neurogenic inflammation.
Accordingly, compunds capable of antagonizing the effects of substance-P at NK.sub.1 receptors will be useful in treating or preventing a variety of brain disorders including pain, anxiety, panic, depression, schizophrenia, neuralgia, and addiction disorders; inflammatory diseases such as arthritis, asthama, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including Parkinson's disease, multiple sclerosis, and Alzheimer's disease; and ophthalmic diseases including scleroderma.
The compounds of the invention, NK.sub.1 receptor antagonists, are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth. They will also be useful as agents for imaging NK.sub.1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
They will also be useful as antiemetics versus emergens such as cisplatin.
International Publication Numbers WO 93/01169, WO 93/01165, and WO 93/001160 cover certain nonpeptide tachykinin receptor antagonists.
Copending U.S. application No. 08/344,064 filed Nov. 29, 1994, covers certain NK.sub.1 receptor antagonists which are unique in the alkylation/substitution pattern along the backbone. That application for a patent is hereby incorporated by reference.